Combinations of adrenergic receptor agonists for the treatment of type 2 diabetes

Abstract

There is herein provided pharmaceutical formulations and kits-of-parts comprising a β2-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and a β3-adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof. This combination of active agents finds particular utility in the treatment of type 2 diabetes.

1 . A pharmaceutical formulation comprising:
 (a) a β 2 -adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof; and   (b) a β 3 -adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipient.   
     
     
         2 . The pharmaceutical formulation as claimed in  claim 1 , wherein the β 2 -adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, bitolterol, salbutamol, levosalbutamol, terbutaline, metaproterenol, pirbuterol, bambuterol, fenoterol, methoxyfenoterol, isoprenaline, procaterol, ritodrine, indacaterol, olodaterol, colterol, hexaprenaline, carmoterol, isoxsuprine, isoetarine, zinterol, bamethane, clencyclohexerol, tulobuterol, BRL-47672, trantinterol, clenproperol, clenpenterol, brombuterol, ractopamine and abediterol, and pharmaceutically acceptable salts thereof. 
     
     
         3 . The pharmaceutical formulation as claimed in  claim 1 , wherein the β 2 -adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, vilanterol, zilpaterol, clenbuterol, (R)-clenbuterol, indacaterol, olodaterol, carmoterol, bamethane, clencyclohexerol, tulobuterol, trantinterol and abediterol, and pharmaceutically acceptable salts thereof. 
     
     
         4 . The pharmaceutical formulation as claimed in  claim 1 , wherein the β 2 -adrenergic receptor agonist is selected from the group consisting of formoterol, arformoterol, salmeterol, (R)-salmeterol, clenbuterol, (R)-clenbuterol, bamethane, trantinterol and abediterol, and pharmaceutically acceptable salts thereof. 
     
     
         5 . The pharmaceutical formulation as claimed in  claim 1 , wherein the β 2 -adrenergic receptor agonist is a long-acting β 2 -adrenergic receptor agonist or an ultra-long-acting β 2 -adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The pharmaceutical formulation as claimed in  claim 1 , wherein the β 2 -adrenergic receptor agonist is clenbuterol, or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The pharmaceutical formulation as claimed in  claim 1 , wherein the β 3 -adrenergic receptor agonist is selected from the group consisting of BRL-37344, BRL-35135, mirabegron, amirabegron, SR59104A, SR59119A, solabegron, vibegron, CAS: 1269433-49-9, CAS: 1269433-05-7, MK-0634, ritobegron, BMS-187257, CL 316,243, CGP 12177, L-755,507, L-742,791, L-750,355, L-749,372, SB-226552, SB-251023, ICI-D 7114, FR 149175, Ro40-2148, CAS: 769118-12-9, rafabegron, BMS-196085, trecadrine, SB-418790 and CAS: 99151-51-6, and pharmaceutically acceptable salts thereof. 
     
     
         8 . The pharmaceutical formulation as claimed in  claim 1 , wherein the β 3 -adrenergic receptor agonist is selected from the group consisting of BRL-37344, BRL-35135, mirabegron, amirabegron, solabegron, vibegron, CAS: 1269433-49-9, CAS: 1269433-05-7 and ritobegron, and pharmaceutically acceptable salts thereof. 
     
     
         9 . The pharmaceutical formulation as claimed in  claim 1 , wherein the β 3 -adrenergic receptor agonist is selected from the group consisting of mirabegron, vibegron, CAS: 1269433-49-9 and CAS: 1269433-05-7, and pharmaceutically acceptable salts thereof. 
     
     
         10 . The pharmaceutical formulation as claimed in  claim 1 , wherein the β 3 -adrenergic receptor agonist is mirabegron, or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The pharmaceutical formulation as claimed in  claim 1 , wherein the β 2 -adrenergic receptor agonist is clenbuterol, or a pharmaceutically acceptable salt thereof, and the β 3 -adrenergic receptor agonist is mirabegron, or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A kit-of-parts comprising components:
 (A) a pharmaceutical formulation comprising a β 2 -adrenergic receptor agonist as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, optionally in admixture with a pharmaceutically acceptable excipient; and   (B) a pharmaceutical formulation comprising a β 3 -adrenergic receptor agonist as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, optionally in admixture with a pharmaceutically acceptable excipient,   which components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other.   
     
     
         13 . A kit-of-parts comprising:
 (I) one of components (A) or (B) as defined in  claim 12 ; and   (II) instructions to use that component in conjunction with the other of the two components.   
     
     
         14 - 15 . (canceled) 
     
     
         16 . A method of treating type 2 diabetes, which method comprises administering a therapeutically effective amount of the pharmaceutical formulation as claimed in  claim 1  to a patient in need of such treatment. 
     
     
         17 . A method of treating type 2 diabetes, which method comprises the administration of a therapeutically effective amount of a β 2 -adrenergic receptor agonist as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a β 3 -adrenergic receptor agonist as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, to a patient in need thereof. 
     
     
         18 - 21 . (canceled)